EP3967679A1 - Novel inhibitors of meprin alpha and beta - Google Patents

Novel inhibitors of meprin alpha and beta Download PDF

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Publication number
EP3967679A1
EP3967679A1 EP21195295.7A EP21195295A EP3967679A1 EP 3967679 A1 EP3967679 A1 EP 3967679A1 EP 21195295 A EP21195295 A EP 21195295A EP 3967679 A1 EP3967679 A1 EP 3967679A1
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Prior art keywords
methyl
compound
group
gradient
hplc
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German (de)
English (en)
French (fr)
Inventor
Michael Wermann
Stephan Schilling
Dagmar Schlenzig
Daniel Ramsbeck
Mirko Buchholz
Hans-Ulrich Demuth
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Vivoryon Therapeutics AG
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Vivoryon Therapeutics AG
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/18—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring

Definitions

  • the present invention relates to novel hydroxamic acid derivatives as inhibitors of meprin ⁇ and/or ⁇ , pharmaceutical compositions comprising such compounds, methods for treatment or prophylaxis of diseases or conditions, especially such that are related to meprin ⁇ and/or ⁇ , and compounds and pharmaceutical compositions for use in such methods.
  • Meprin ⁇ and ⁇ both represent zinc-dependent metalloproteases of the astacin family and the metzincin superfamily. They show a similar domain structure and the human enzymes are of 45% sequence homology to each other. Meprin ⁇ is a type 1 transmembrane protein with extracellular protease activity whereas meprin ⁇ is shed during the secretory pathway and secreted into extracellular space. Both enzymes are expressed as zymogens with high expression rates in epithelial cells of the kidney and intestine, and they have been demonstrated in intestinal leukocytes, skin and certain cancer cells.
  • the meprins show distinct substrate specificity with a preference of acidic amino acids in the P1'-position ( Becker-Pauly, C.; Barre, O.; Schilling, O.; auf dem Keller, U.; Ohler, A.; Broder, C. et al. (2011), Mol.Cell Proteomics, doi: 10.1074/mcp.M111.009233 ).
  • a number of in vitro substrates have been identified including extracellular matrix proteins, peptide hormones and cytokines.
  • meprin ⁇ Known in vitro substrates of meprin ⁇ comprise orcokinin, gastrin 17, Peptide YY, kinetensin, osteopontin, interleukin 1 ⁇ , APP, MUC 2 mucin, and cystic fibrosis transmembrane conductance regulator E-cadherin
  • known in vitro substrates of meprin ⁇ comprise bombesin, neurotensin, Substance P, angiotensin I, luteinizing hormone releasing hormone, valosin, vasoactive intestinal peptide, bradykinin, ⁇ -melanocyte stimulating hormone, MCP-1, and occludin.
  • Known in vitro substrates of both meprin ⁇ and ⁇ are, e.g., the Gastrin-releasing peptide, and Cholecystokinin.
  • Meprin ⁇ has been shown to act as ⁇ -secretase of amyloid precursor protein to form amyloid ⁇ (A ⁇ ) peptides in vitro ( Bien, Jessica; Jefferson, Tamara; Causevi ⁇ , Mirsada; Jumpertz, Thorsten; Munter, Lisa; Multhaup, Gerd et al. (2012), The Journal of biological chemistry 287 (40), pp. 33304-33313 ).
  • a ⁇ peptide which is abundantly found in the brains of patients suffering from Alzheimer's disease, is central in the pathogenesis of this disease.
  • meprin ⁇ is capable of formation of N- terminally truncated A ⁇ and therefore might be involved in the generation of potentially more toxic species of A ⁇ . Accordingly, meprin ⁇ appears to be involved in the pathogenesis and/or disease progression of, e.g., Alzheimer's disease.
  • meprin ⁇ and ⁇ appear to be involved in the pathogenesis and/or disease progression of, e.g., nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, and bladder inflammation.
  • meprin ⁇ and ⁇ appear be involved in the pathogenesis and/or disease progression of, e.g., fibrosis and fibrotic conditions (keloids, pulmonary hypertension) and interstitial lung disease (ILD).
  • fibrosis and fibrotic conditions keloids, pulmonary hypertension
  • ILD interstitial lung disease
  • Meprin ⁇ has been shown to be a susceptibility gene for IBD (Crohn's disease, ulcerative colitis) and that its absence increases chronic inflammation, while meprin ⁇ has pro-inflammatory activity and its lack results in some protection from injury ( Banerjee, Sanjita; Jin, Ge; Bradley, S. Gaylen; Matters, Gail L.; Gailey, Ryan D.; Crisman, Jacqueline M.; Bond, Judith S. (2011), Am. J. Physiol. Gastrointest. Liver Physiol. 300 (2), pp. G273-82 ). Accordingly, meprin ⁇ and ⁇ appear to be involved in the pathogenesis and/or disease progression of, e.g., chronic inflammation, Crohn's disease, ulcerative colitis, and inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the present invention aims, as a main object, to provide potent inhibitors of meprin ⁇ and/or ⁇ .
  • a first object of the present invention is to provide selective inhibitors of meprin ⁇ .
  • a second object of the present invention is to provide selective inhibitors of meprin ⁇ .
  • a third object of the present invention is to provide dual inhibitors of meprin ⁇ and ⁇ .
  • a fourth object of the present invention is to provide meprin inhibitors according to any of the aforementioned objects, wherein the inhibitors have acceptable drug-like properties.
  • a fifth object of the present invention is to provide a pharmaceutical composition comprising a meprin inhibitor according to any of the aforementioned objects that is suitable for administration to a subject in need thereof.
  • a sixth object of the present is to provide a method for producing the meprin inhibitors according to any of the aforementioned objects.
  • a seventh object of the present is to provide a method for treatment or prophylaxis of the human or animal body, and a compound or a pharmaceutical composition for use in such a method.
  • An eight object of the present is to provide a method for treatment or prophylaxis of a subject suffering from or having risk of developing a disease or condition related to meprin ⁇ and/or ⁇ .
  • a ninth object of the present is to provide a method for treatment or prophylaxis of a subject suffering from or having risk of developing a disease or condition such as Alzheimer's disease, nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, bladder inflammation, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, chronic inflammation, colitis, fibrosis, fibrotic conditions, keloids, pulmonary hypertension, or interstitial lung disease (ILD), or cancer, especially colorectal cancer, and/or a compound for use in such a method.
  • a disease or condition such as Alzheimer's disease, nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, bladder inflammation, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, chronic inflammation, colitis, fibrosis, fibrotic conditions, keloids, pulmonary hypertension, or interstitial lung
  • the present invention provides a compound represented by the following Formula I, its individual enantiomers, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof, wherein:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to above Formula I, its individual enantiomers, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • the present invention also provides a method for producing the above compounds.
  • the present invention also provides a method for treatment or prophylaxis of the human or animal body by surgery or therapy comprising administering a therapeutically effective amount of the above compound or pharmaceutical composition to a subject in need thereof, and/or a compound or pharmaceutical composition for use in such a method.
  • the present invention also provides a method for treatment or prophylaxis of Alzheimer's disease, nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, bladder inflammation, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, chronic inflammation, colitis, fibrosis, fibrotic conditions, keloids, pulmonary hypertension, interstitial lung disease (ILD), or cancer, especially colorectal cancer, comprising administering a therapeutically effective amount of the above compound or pharmaceutical composition to a subject in need thereof, and/or a compound or pharmaceutical composition for use in such a method.
  • IBD inflammatory bowel disease
  • Crohn's disease Crohn's disease
  • ulcerative colitis chronic inflammation
  • colitis colitis
  • fibrosis fibrotic conditions
  • keloids pulmonary hypertension
  • ILD interstitial lung disease
  • cancer especially colorectal cancer
  • subject refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, prophylaxis, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • alkyl denotes a C 1-12 alkyl group, suitably a C 1-8 alkyl group, e.g. C 1-6 alkyl group, e.g. C 1-4 alkyl group.
  • Alkyl groups may be straight chain or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (e.g. n-pentyl), hexyl (e.g. n-hexyl), heptyl (e.g. n-heptyl) and octyl (e.g. n-octyl).
  • alkyl as used herein also comprises cycloalkyl groups.
  • cycloalkyl denotes a C 3-10 cycloalkyl group (i.e. 3 to 10 ring carbon atoms), more suitably a C 3- 8 cycloalkyl group, e.g. a C 3-6 cycloalkyl group.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • a most suitable number of ring carbon atoms is three to six.
  • alk for example in the expressions “alkoxy”, “haloalkyl” and “thioalkyl” should be interpreted in accordance with the definition of "alkyl".
  • alkoxy groups include methoxy, ethoxy, propoxy (e.g. n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), hexoxy (e.g. n-hexoxy), heptoxy (e.g. n-heptoxy) and octoxy (e.g. n-octoxy).
  • exemplary thioalkyl groups include methylthio.
  • haloalkyl groups include fluoroalkyl e.g.
  • exemplary haloalkoxy groups include fluoroalkyl e.g. OCF 3 .
  • fluoro(C 1-6 alkyl) and fluoro(C 1-6 alkoxy) denote a C 1-6 alkyl and C 1-6 alkoxy group, respectively, each of which is substituted by one or more fluoro atoms.
  • alkenyl denotes a C 2-12 alkenyl group, suitably a C 2-6 alkenyl group, e.g. a C 2-4 alkenyl group, which contains at least one double bond at any desired location and which does not contain any triple bonds.
  • Alkenyl groups may be straight chain or branched.
  • Exemplary alkenyl groups including one double bond include propenyl and butenyl.
  • Exemplary alkenyl groups including two double bonds include pentadienyl, e.g. (1 E, 3E)-pentadienyl.
  • alkenyl as used herein also comprises cycloalkenyl groups.
  • cycloalkenyl unless specifically limited, denotes a C 5 -io cycloalkenyl group (i.e. 5 to 10 ring carbon atoms), more suitably a C 3-6 cycloalkenyl group e.g. a C 5-6 cycloalkenyl group.
  • Exemplary cycloalkenyl groups include cyclopropenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. A most suitable number of ring carbon atoms is five to six.
  • alkynyl denotes a C 2-12 alkynyl group, suitably a C 2-6 alkynyl group, e.g. a C 2-4 alkynyl group, which contains at least one triple bond at any desired location and may or may not also contain one or more double bonds.
  • Alkynyl groups may be straight chain or branched.
  • Exemplary alkynyl groups include propynyl and butynyl.
  • alkylene denotes a chain of formula -(CH 2 ) n -wherein n is an integer e.g. 2-5, unless specifically limited.
  • Carbocyclyl denotes any ring system in which all the ring atoms are carbon and which contains between three and twelve ring carbon atoms, suitably between three and ten carbon atoms and more suitably between three and eight carbon atoms.
  • Carbocyclyl groups may be saturated or partially unsaturated, but do not include aromatic rings. Examples of carbocyclyl groups include monocyclic, bicyclic, and tricyclic ring systems, in particular monocyclic and bicyclic ring systems. Other carbocylcyl groups include bridged ring systems (e.g. bicyclo[2.2.1 ]heptenyl).
  • a specific example of a carbocyclyl group is a cycloalkyl group. A further example of a carbocyclyl group is a cycloalkenyl group.
  • aryl denotes a C 6-12 aryl group, suitably a C 6-10 aryl group, more suitably a C 6-8 aryl group.
  • Aryl groups will contain at least one aromatic ring (e.g. one, two or three rings).
  • An example of a typical aryl group with one aromatic ring is phenyl.
  • An example of a typical aryl group with two aromatic rings is naphthyl.
  • arylalkyl unless specifically limited, denotes an aryl residue which is connected via an alkylene moiety, e.g., a C 1-4 alkylene moiety.
  • heterocyclyl refers to a carbocyclyl group wherein one or more (e.g. 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O.
  • a specific example of a heterocyclyl group is a cycloalkyl group (e.g. cyclopentyl or more particularly cyclohexyl) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or O.
  • heterocyclyl groups containing one hetero atom include pyrrolidine, tetrahydrofuran and piperidine, and exemplary heterocyclyl groups containing two hetero atoms include morpholine and piperazine.
  • a further specific example of a heterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S and O.
  • An example of such a group is dihydropyranyl (e.g. 3,4-dihydro-2H-pyran-2-yl-).
  • heteroaryl denotes an aryl residue, wherein one or more (e.g. 1 , 2, 3, or 4, suitably 1 , 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O, or else a 5-membered aromatic ring containing one or more (e.g. 1 , 2, 3, or 4, suitably 1 , 2 or 3) ring atoms selected from N, S and O.
  • exemplary monocyclic heteroaryl groups having one heteroatom include: five membered rings (e.g. pyrrole, furan, thiophene); and six membered rings (e.g.
  • pyridine such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl
  • exemplary monocyclic heteroaryl groups having two heteroatoms include: five membered rings (e.g. pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-yl imidazol-4-yl); six membered rings (e.g. pyridazine, pyrimidine, pyrazine).
  • Exemplary monocyclic heteroaryl groups having three heteroatoms include: 1 ,2,3-triazole and 1 ,2,4-triazole.
  • Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole.
  • Exemplary bicyclic heteroaryl groups include: indole (e.g. indol-6-yl), benzofuran, benzthiophene, quinoline, isoquinoline, indazole, benzimidazole, benzthiazole, quinazoline and purine.
  • heteroarylalkyl denotes a heteroaryl residue which is connected via an alkylene moiety e.g. a C 1-4 alkylene moiety.
  • halogen or halo
  • fluorine F
  • chlorine CI
  • bromine Br
  • amino refers to the group -NH 2 .
  • substitutions refer to (optional) substitution by one or several groups independently selected from a halogen atom, a cyano group, a hydroxyl group and a carboxyl group. These terms also refer to (optional) substitution by one or several groups independently selected from -C(O)-O-(C 1-6 alkyl) group, a -C(O)-NH 2 group, a C 1-6 alkylsulfono group, C 1-6 alkoxy and a C 1-6 aliphatic, aromatic or heterocyclic group, each of which may be further substituted by one or several halogen atoms, carboxyl, cyano, and/or hydroxyl groups.
  • an alkyl group which is substituted does not have a keto group on the C atom that is directly bound to the N atom in Formula I.
  • alkoxyaryl denotes an aryl residue which is substituted by at least one alkoxy, carboxy, cyano, halo, hydroxy and heteroaryl group, respectively.
  • alkoxyheteroaryl denotes a heteroaryl residue which is substituted by at least one alkoxy, carboxy, cyano, halo, and hydroxy group, respectively.
  • arylmethyl unless specifically limited, denotes an aryl residue which is connected via a methylene moiety.
  • Stereoisomers All possible stereoisomers of the claimed compounds are included in the present invention.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • stereoisomers Where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base, or by salt formation with an optically active base, such as quinine, quinidine, quinotoxine, cinkotoxine, (S)-phenylethylamine, (1 R ,2 S )-ephedrine, (R)-phenylglycinol, (S)-2-aminobutanol, followed by fractional crystallization and regeneration of the free acid.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using
  • Polymorph crystal forms Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • tautomer refers to the migration of protons between adjacent single and double bonds. The tautomerization process is reversible. Compounds described herein can undergo any possible tautomerization that is within the physical characteristics of the compound.
  • the term “pharmaceutically acceptable” embraces both human and veterinary use.
  • pharmaceutically acceptable embraces a veterinarily acceptable compound or a compound acceptable in human medicine and health care.
  • Salts, hydrates and solvates of the compounds of Formula I and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable.
  • salts, hydrates and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts, hydrates and solvates.
  • Suitable salts according to the invention include those formed with both organic and inorganic acids or bases.
  • Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for example p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic or naphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.
  • the present invention further includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound.
  • the term “administering” shall encompass the treatment of the various disorders described with prodrug versions of one or more of the claimed compounds, but which converts to the above specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in " Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985 .
  • composition is intended to encompass a product comprising the claimed compounds in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the claimed compounds.
  • suitable carriers and additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Carriers which can be added to the mixture, include necessary and inert pharmaceutical excipients, including, but not limited to, suitable binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, coatings, disintegrating agents, dyes and coloring agents.
  • Soluble polymers as targetable drug carriers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Protective Groups During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973 ; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , fully incorporated herein by reference. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • a protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction.
  • Protecting groups are e.g. alcohol protecting groups, amine protecting groups, carbonyl protecting groups, carboxylic acid protecting groups and phosphate protecting groups.
  • alcohol protecting groups are acetyl (Ac), benzoyl (Bz), benzyl (Bn, Bnl) ⁇ -methoxyethoxymethyl ether (MEM), mimethoxytrityl [bis-(4-methoxyphenyl)phenylmethyl, DMT], methoxymethyl ether (MOM), methoxytrityl [(4-methoxyphenyl)diphenylmethyl, MMT), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), trityl (triphenylmethyl , Tr), silyl ethers (such as trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBDMS), tert-butyldimethylsilyloxymethyl ether (TOM), and triisopropylsilyl ether (TIPS)
  • Suitable amine protecting groups are selected from carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), ie f-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), and other sulfonamides (Nosyl & Nps).
  • Suitable carbonyl protecting groups are selected from acetals and ketals, acylals and dithianes.
  • Suitable carboxylic acid protecting groups are selected from methyl esters, benzyl esters, tert-butyl esters, silyl esters, orthoesters, and oxazoline.
  • phosphate protecting groups are 2-cyanoethyl and methyl (Me)
  • the present invention provides a compound represented by the following Formula I, its individual enantiomers, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof, wherein:
  • R 3 and R 4 are preferably the same, and are more preferably joined together to form a carbocyclic or heterocyclic ring.
  • R 3 is preferably H or is preferably selected from the group consisting of C 1-6 alkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which can be optionally substituted; and more preferably selected from the group consisting of methyl, ethyl, 1-propyl, 2-propyl, benzyl, phenyl carboxymethyl and 2-carboxyethyl.
  • n 2.
  • n 3.
  • n 1.
  • the present invention provides the compound according to aspect 1, wherein R 3 is H.
  • the present invention provides the compound according to any of aspects 1-2, wherein R 1 and R 3 are H.
  • the present invention provides the compound according to any of aspects 1-3, wherein R 1 is selected from the group consisting of arylmethyl, (alkoxyaryl)methyl, (hydroxyaryl)methyl, (carboxyaryl)methyl, (alkoxyheteroaryl)methyl, (heteroarylaryl)methyl, (hydroxyheteroaryl)methyl and (carboxyheteroaryl)methyl, each of which can be optionally substituted.
  • the present invention provides the compound according to any of aspects 1-4, wherein R 1 is represented by the following formula, wherein:
  • the present invention provides the compound according to any of aspects 1-5, wherein R 1 is selected from the group consisting of (1,3-benzodioxol-5-yl)methyl, (3-carboxyphenyl)methyl, (4-carboxyphenyl)methyl,(2,4-difluoro-3-hydroxy-phenyl)-methyl, (3,5-difluoro-4-hydroxyphenyl)methyl, (2,6-difluoro-3-hydroxy-phenyl)methyl, (4-fluoro-3-hydroxy-phenyl)methyl, (2-fluoro-3-hydroxy-phenyl)methyl, (4-chloro-2-fluoro-3-hydroxy-phenyl)-methyl, (4-chloro-2-fluoro-3-hydroxy-phenyl)-methyl, (4-chloro-2-fluoro-3-methoxyphenyl)-methyl, (2,4-difluoro-3-methoxy-phenyl)methyl, (3-ethoxycarbonylphenyl)methyl, (4
  • the present invention provides the compound according to any of aspects 1-6, wherein R 2 is selected from the group consisting of aryl, alkoxyaryl, carboxyaryl, cyanoaryl, haloaryl, hydroxyaryl, alkoxyheteroaryl, cyanoheteroaryl, haloheteroaryl, heteroarylaryl, hydroxyheteroaryl and carboxyheteroaryl, each of which can be optionally substituted.
  • the present invention provides the compound according to any of aspects 1-7, wherein R 2 is represented by the following formula, wherein:
  • the present invention provides the compound according to any of aspects 1-8, wherein R 2 is selected from the group consisting of 1,3-benzodioxol-5-yl, 3-carboxyphenyl, 1,3-benzodioxol-5-yl, 3-carboxyphenyl, 4-carboxyphenyl, 3-carboxy-4-methoxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 4-chlorophenyl, 4-cyanophenyl, 4-fluorophenyl, 2,6-difluoro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-methylphenyl, 2,4-difluoro-3-hydroxy-phenyl, 3,5-difluoro-4-hydroxy-phenyl, 2,6-difluoro-3-hydroxy-phenyl, 4-fluoro-3-hydroxyphenyl, 2-fluoro-3
  • the present invention provides the compound according to any of aspects 1-9, wherein:
  • the present invention provides a compound of Formula V: wherein R 1 , R 2 , R 3 and R 4 are defined as with respect to the above Formula I, with the proviso that R 1 is not H.
  • R 1 can be H.
  • the present invention provides the compound according to aspect 11, wherein R 3 is H.
  • the present invention provides the compound according to aspects 11-12, wherein R 3 and R 4 are H.
  • the present invention provides the compound according to any of aspects 11-13, wherein R 1 is selected from the group consisting of arylmethyl, (alkoxyaryl)methyl, (hydroxyaryl)methyl, (carboxyaryl)methyl, (alkoxyheteroaryl)methyl, (heteroarylaryl)methyl, (hydroxyheteroaryl)methyl and (carboxyheteroaryl)methyl, each of which can be optionally substituted.
  • R 1 is represented by the following formula, wherein:
  • the present invention provides the compound according to any of aspects 11-15, wherein R 1 is selected from the group consisting of (1,3-benzodioxol-5-yl)methyl, (3-carboxyphenyl)methyl, and (4-carboxyphenyl)methyl; preferably (3-carboxyphenyl)methyl.
  • the present invention provides the compound according to any of aspects 11-16, wherein R 2 is selected from the group consisting of aryl, alkoxyaryl, carboxyaryl, cyanoaryl, haloaryl, hydroxyaryl, alkoxyheteroaryl, cyanoheteroaryl, haloheteroaryl, heteroarylaryl, hydroxyheteroaryl and carboxyheteroaryl, each of which can be optionally substituted.
  • the present invention provides the compound according to any of aspects 38-44, wherein R 2 is represented by the following formula, wherein:
  • the present invention provides the compound according to any of aspects 11-17, wherein R 2 is selected from the group consisting of 1,3-benzodioxol-5-yl, 3-carboxyphenyl, 1,3-benzodioxol-5-yl, 3-carboxyphenyl, 4-carboxyphenyl, 3-carboxy-4-methoxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 4-chlorophenyl, 4-cyanophenyl, 4-fluorophenyl, 2,6-difluoro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, and 4-methylphenyl.
  • R 2 is selected from the group consisting of 1,3-benzodioxol-5-yl, 3-carboxyphenyl, 1,3-benzodioxol-5-yl, 3-carboxyphenyl, 4-car
  • the present invention provides the compound according to any of aspects 11-18, wherein:
  • the compound according to the present invention is most preferably selected from the group consisting of: or (ii) selected from the group consisting of:
  • Aspect 21 of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to any of the preceding aspects, its individual enantiomers, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient as defined above.
  • the present invention provides a compound or a pharmaceutical composition according to any of the above aspects for use in a method for treatment or prophylaxis of the human or animal body by surgery or therapy.
  • the present invention also provides a method for treatment or prophylaxis of the human or animal body by surgery or therapy comprising administering a therapeutically effective amount of the compound or pharmaceutical composition according to any of the above aspects to a subject in need thereof.
  • the present invention also provides compound or a pharmaceutical composition according to any of the above aspects for use in a method for treatment or prophylaxis of Alzheimer's disease, nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, bladder inflammation, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, chronic inflammation, colitis, fibrosis, fibrotic conditions, keloids, pulmonary hypertension, interstitial lung disease (ILD), or cancer, especially colorectal cancer.
  • IBD inflammatory bowel disease
  • Crohn's disease Crohn's disease
  • ulcerative colitis chronic inflammation
  • colitis colitis
  • fibrosis fibrotic conditions
  • keloids pulmonary hypertension
  • ILD interstitial lung disease
  • the present invention also provides a method for treatment or prophylaxis of Alzheimer's disease, nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, bladder inflammation, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, chronic inflammation, colitis, fibrosis, fibrotic conditions, keloids, pulmonary hypertension, interstitial lung disease (ILD), or cancer, especially colorectal cancer, comprising administering a therapeutically effective amount of the compound or pharmaceutical composition according to any of the above aspects to a subject in need thereof.
  • IBD inflammatory bowel disease
  • Crohn's disease Crohn's disease
  • ulcerative colitis chronic inflammation
  • colitis colitis
  • fibrosis fibrotic conditions
  • keloids pulmonary hypertension
  • ILD interstitial lung disease
  • cancer especially colorectal cancer
  • the present invention also provides the following methods for producing the compounds according to Formulae I-V.
  • Compounds of Formula I or V can be obtained by reacting he respective Fmoc-amino acid with tritylhydroxylamine in a suitable solvent, such as DMF, followed by addition of an activating agent, such as TBTU, and a base, such as DIPEA, followed by addition of water, collecting the resulting precipitate by filtration, optionally washing the precipitate with an organic solvent, such as an ether, and optionally with an aqueous base solution. The residue is then redissolved in a suitable organic solvent, such as THF, (and treated with a base, such as DBU, followed by optionally removing the solvent, and optionally purifying the residue.
  • a suitable organic solvent such as THF
  • a base such as DBU
  • Compounds of Formula I or V can be obtained by reacting at room temperature (Method B) or at elevated temperature (Method C), optionally under microwave irradiation at 140°C, the respective trityl protected hydroxamic acid with a base and the respective halide, preferably an optionally substituted benzyl halide, and optionally: extracting with an organic solvent, drying the combined organic phases removing the solvent, and purifying the residue; followed by treating the residue with triisopropylsilane and TFA; and optionally: extracting with an organic solvent, drying the combined organic phases, removing the solvent, and purifying the residue.
  • Compounds of Formula I or V can be obtained by reacting a suitable aldehyde (depending on R 1 ) with the trityl protected hydroxamic acid; then adding sodium borohydride; and optionally: extracting with an organic solvent, drying the combined organic phases removing the solvent, and purifying the residue, to obtain a trityl protected hydroxamic acid derivative (Method D); then reacting the trityl protected hydroxamic acid derivative with a base and the respective halide, preferably an optionally substituted benzyl halide, at room temperature (Method E) or at elevated temperature, optionally under microwave irradiation at 140°C (Method F); and optionally: extracting with an organic solvent, drying the combined organic phases, removing the solvent, and purifying the residue; followed by treating the residue with triisopropylsilane and TFA; and optionally: extracting with an organic solvent, drying the combined organic phases, removing the solvent, and purifying the residue.
  • Compounds of Formula I or V can be obtained by reacting an amino acid ester and a respective aldehyde in a suitable solvent, treating with a reducing agent, such as sodium triacetoxy borohydride, and optionally a catalytic amount of acetic acid, followed by addition of water, extracting with an organic solvent, drying the combined organic phases removing the solvent, and purifying the residue (Method G).
  • a reducing agent such as sodium triacetoxy borohydride
  • acetic acid optionally a catalytic amount of acetic acid
  • the respective amino acid ester derivative obtained by method G is dissolved a suitable solvent followed by addition of hydroxylamine hydrochloride and a base, such as sodium methanoxide, and preferably heating the mixture until completion, optionally under microwave irradiation at 80°C, followed by addition of water, extracting with an organic solvent, drying the combined organic phases removing the solvent, and purifying the residue.
  • a suitable solvent such as sodium methanoxide
  • the compound was synthesized starting from Fmoc-Gly-OH (2.97 g, 10 mmol, 1 eq), Tritylhydroxylamine (2.8 g, 10 mmol, 1 eq), TBTU (3.21 g, 10 mmol, 1 eq), DIPEA (3.5 ml, 20 mmol, 2 eq) and DBU (2.2 ml, 15 mmol, 1.5 eq) according to method A. Yield: 1.4 g (42.1%), ESI-MS: m/z 243.2 [Trityl] + , 333.3 [M+H] + ; HPLC (gradient 2): rt 12.24 min (100%).
  • Step 2 3-[[(3-Carboxyphenyl)methyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid
  • the compound was synthesized starting from 2-Amino-N-trityloxy-acetamide (332 mg, 1 mmol, 1eq), tert-butyl 3-(chloromethyl)benzoate (499 mg, 2.2 mmol, 2.2 eq) and TEA (305 ⁇ l, 2.2 mmol, 2.2 eq) followed by acidic deprotection and purification by semi-preparative HPLC as described in method B.
  • the trityl protected hydroxamic acid derivative (1 eq) obtained by method D was dissolved in DMF (5 ml/ mmol). Triethylamine (1.1 eq) and the respective benzyl halide (1.1 eq) were added and the mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted with EtOAc (3x25 ml). The combined organic layers were dried over Na 2 SO 4 and evaporated. The residue was treated with CH 2 Cl 2 /TFA (1:1 v/v, 5 ml) and triisopropysilane (1.5 eq). After stirring at room temperature for 2 hours, the volatiles were evaporated.
  • the residue was purified by semi-preparative HPLC (Varian Prostar, Phenomenex Luna C 18 (2) column, H 2 O/MeCN gradient containing 0.04% TFA) or by flash chromatography (silica, CHCl 3 /MeOH gradient).
  • the trityl protected hydroxamic acid derivative (1 eq) obtained by method D was dissolved in DMF (5 ml/ mmol). Triethylamine (1.1 eq) and the respective benzyl halide (1.1 eq) were added and the mixture was heated to 120°C under microwave irradiation for 15 min. After cooling to room temperature, the reaction was diluted with water and extracted with EtOAc (3 ⁇ 25 ml). The combined organic layers were dried over Na 2 SO 4 and evaporated. The residue was treated with CH 2 Cl 2 /TFA (1:1 v/v, 5 ml) and triisopropysilane (1.5 eq). After stirring at room temperature for 2 hours, the volatiles were evaporated.
  • the residue was purified by semi-preparative HPLC (Varian Prostar, Phenomenex Luna C 18 (2) column, H 2 O/MeCN gradient containing 0.04% TFA) or by flash chromatography (silica, CHCl 3 /MeOH gradient).
  • the compound was synthesized starting from tert-Butyl 3-[[[2-oxo-2-(trityloxyamino)ethyl]amino]-methyl]benzoate (method D - see above, 410 mg, 0.78 mmol, 1 eq), 4-Bromomethylbenzoic acid tert butyl ester (234 mg, 0.86 mmol, 1.1 eq) and TEA (120 ⁇ l, 0.86 mmol, 1.1 eq) and purified by semi-preparative HPLC according to method E.
  • the amino acid ester (1 eq) and the respective aldehyde (3 eq) were suspended in dichloromethane (20 ml/mmol) and treated with sodium triacetoxy borohydride (4 eq) and a catalytic amount of acetic acid. The mixture was stirred at room temperature overnight. The reaction was quenched by addition of water and extracted with EtOAc (3x25 ml). The combined organic layers were dried over Na 2 SO 4 and evaporated. The residue was purified by flash chromatography (silica, heptane/diethyl ether gradient).
  • the respective amino acid ester derivative (1 eq) obtained by method G was dissolved in MeOH (6-10 ml). Hydroxylamine hydrochloride (3 eq) and sodium methanoxide (6 eq) were added and the mixture was heated in a microwave (Biotage ® initiator+) at 80°C upon completion (usually 6-10 min). After cooling to room temperature the mixture was diluted with water. The pH was adjusted to ⁇ 8 by means of diluted aqueous HCl and the mixture was extracted with EtOAc (3 ⁇ 25 ml). The combined organic layers were dried over Na 2 SO 4 and evaporated. The residue was purified by semi-preparative HPLC (Varian Prostar, Phenomenex Luna C 18 (2) column, H 2 O/MeCN gradient containing 0.04% TFA).
  • the compound was synthesized starting from glycine methylester hydrochloride (126 mg, 1 mmol, 1 eq), 1,4-Benzodioxane-6-carbaldehyde (492 mg, 3 mmol, 3 eq) and sodium triacetoxy borohydride (848 mg, 4 mmol 4 eq) according to method G. Yield: 322 mg (83,5 %), ESI-MS: m/z 386.9 [M+H] + ; HPLC (gradient 2): rt 11.09 min (97.2%)
  • Step 2 2-[bis(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)amino]ethanehydroxamic acid
  • the compound was synthesized starting from Methyl 2-[bis(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]acetate (322 mg, 0.84 mmol, 1 eq), NH2OH*HCl (175 mg, 2.5 mmol, 3 eq) and sodium methoxide (0.9 ml 30% in MeOH, 5 mmol, 6 eq) according to method H.
  • the compounds were analyzed using a gradient at a flow rate of 1 mL/min; whereby eluent (A) was acetonitrile, eluent (B) was water, both containing 0.04 % (v/v) trifluoroacetic acid applying one of the following gradients:
  • enzymatic activity was based on the cleavage of internally quenched peptide substrates.
  • a typical assay of 250 ⁇ l total volume measured in black 96 well plates consisted of 100 ⁇ l buffer, 50 ⁇ lenzyme at a final concentration of 5e-8 M to 5e-9 M, 50 ⁇ lsubstrate (0.15 to 80 ⁇ M, in buffer, 0.5% DMSO) and 50 ⁇ l inhibitor solution (in buffer, 1% DMSO). In case of 125 ⁇ l assay volume (black 96 half area well plates) all volumes were cut in half.
  • Enzymatic activity of ADAMs was measured in 384 well plates with 60 ⁇ l total assay volume consisting of 20 ⁇ l inhibitor, 20 ⁇ l buffer, 10 ⁇ l enzyme and 10 ⁇ l substrate.
  • Ki values were assessed combining 4 substrate concentrations (5-40 ⁇ M) with at least 5 inhibitor concentrations.
  • IC50 values the influence of 12 inhibitor concentrations ranging from 0 to 5e-5 M on the enzymatic activity was investigated in the presence of one standard substrate concentration (10 ⁇ M).
  • Initial velocities were determined and converted into concentration units applying a standard curve obtained after complete conversion of different substrate concentrations under assay conditions. All measurements were performed using a fluorescence plate reader (FLUOstar OPTIMA, BMG Labtech) at 30°C.
  • the kinetic parameters were determined at least in duplicates on separate days.
  • the excitation/emission wavelength was 340/420 nm.
  • the kinetic data was evaluated using GraFit software (version 7.0.3, Erithacus Software).
  • MMPs were activated prior to measurement by APMA (p-aminophenylmercuric acetate) treatment according to manufacturer's instructions (R&D systems).
  • Table 1 Peptide substrates and assay conditions used for determination of enzymatic activity
  • Enzyme Substrate Buffer Assay volume hMeprin ⁇ Abz-YVAEAPK(Dnp)G-OH 40 mM Tris pH 8.0 250 ⁇ l hMeprin ⁇ Abz-YVADAPK(Dnp)G-OH 40 mM HEPES pH 7.4 250 ⁇ l hMMPs 2, 9 and 13 (R&D systems) Mca-PLGL-(DapDnp) -AR-NH 2 50 mM Tris, 2 ⁇ M ZnCl 2 , 150 mM NaCl, pH 7.5 125 ⁇ l hADAMs 10 and 17 (R&D systems) Abz-LANAVRSSSR-(DapDnp) -NH 2
  • IC 50 and K i values for the inhibition of Meprin ⁇ and ⁇ measured using the above enzyme assays are shown in the following Tables.
  • IC 50 refers to the average IC 50 values measured as described above
  • SD (IC50) refers to the standard deviation of the average IC 50 values
  • Ki refers to the average K i values measured as described above
  • SD(Ki) to the standard deviation of the average K i values. Table 2.
  • Example 6 76 17 39 0.2 3435 134 1210 14
  • Example 7 206 32 101 7 44400 4526 n.d. n.d.
  • Example 8 1445 630 1034 292 n.d. n.d. n.d. n.d.
  • Example 9 2250 982 874 156 n.d. n.d. n.d. n.d.
  • Example 10 352 40 157 15 3735 714 1091 227
  • Example 11 355 46 154 2 2120 283 1255 346
  • Example 12 31350 636 n.d. n.d. n.d. n.d. n.d. n.d. n.d.
  • Example 13 41100 4000 n.d. n.d. n.d.
  • Example 14 559 32 288 27 n.d. n.d. n.d. n.d. n.d.
  • Example 15 31800 1600 n.d. n.d. n.d. n.d. n.d. n.d. n.d.
  • Example 16 22800 4384 n.d. n.d. n.d. n.d. n.d. n.d. n.d.
  • Example 17 1285 15 797 185 n.d. n.d. n.d. n.d. n.d.
  • Example 18 361 35 170 11 4670 1 1990 481
  • Example 19 320 7 125 16 4875 615 1950
  • Example 20 76 4 33 5 1795 205 796 55
  • Example 21 177 8 1680 99 4215 460 1680 99
  • Example 22 285 94 105 4 1430 255 606 45
  • Example 23 20000 0 n.d. n.d. 1685 36 n.d. n.d.
  • Example 24 60933 2065 n.d. n.d. 2330 283 n.d. n.d.
  • Example 25 80400 707 n.d. n.d. 4135 347 n.d. n.d.
  • Example 26 53400 3536 n.d. n.d. 1985 148 n.d. n.d.
  • Example 27 34450 2899 n.d. n.d. 3195 2474 n.d. n.d.
  • Example 28 4200 495 3103 422 16700 265 n.d. n.d.
  • Example 29 15800 2687 n.d. n.d. 44367 5424 n.d. n.d.
  • Example 30 15500 990 n.d. n.d. 10245 361 n.d. n.d.
  • Example 31 643 30 165 11 233 36 87 2
  • Example 32 39300 1556 n.d. n.d. 265500 4950 n.d. n.d.
  • Example 33 4255 163 2575 21 45150 1344 n.d. n.d.
  • Example 34 11850 212 n.d. n.d. 29950 778 n.d. n.d.
  • Example 35 2910 141 1355 64 2655 247 n.d. n.d.
  • Example 36 11650 354 n.d. n.d. 21700 1414 n.d. n.d.
  • Example 37 12150 71 n.d. n.d. 26250 354 n.d. n.d.
  • Example 38 742 42 225 27 2610 283 948 22
  • Example 39 654 11 325 10 8660 552 2530 311
  • Example 40 12000 566 n.d. n.d. 1465 120 521 8
  • Example 41 13100 849 n.d. n.d.
  • Example 47 23 1 12 2 626 1 189 15 Example 48 272 20 118 7 1305 120 263 6 Example 49 5515 78 1965 64 5600 156 998 1 Example 50 1060 57 352 8 986 21 306 14 Example 51 2905 7 1170 226 1210 14 335 3 Example 52 24 1 8 0.6 368 8 104 12 Example 53 331 4 158 3 995 21 328 28 Example 54 94850 10112 1755 148 7270 240 n.d. n.d. Example 55 n.d. n.d. n.d. 5660 381 1597 323 Example 56 12800 700 n.d. n.d. 4975 35 1006 91 Example 57 68250 1061 n.d.
  • Example 59 839 30 271 28 4130 1598 1465 148
  • Example 61 20150 354 n.d. n.d. 5320 354 1180 85
  • Example 2 64 74 78 93 76
  • Example 6 68 85 94 87 60
  • Example 7 98 92 79 90
  • Example 10 74 84 64 94 64
  • Example 11 10 24 7
  • Example 18 93 85 59 82 60
  • Example 31 82 79 50 96 71 Example 47 67 94 102 99 82
  • Example 48 87 87 99 92 76
  • Example 52 41 81 93 97 82
  • Example 53 75 73 63 91 59

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